Prions, more than just brain rot.

Prions, self-replicating proteins, the causative agents underlying BSE and CJD, have potentially important roles in evolution and memory formation.

Here in the UK, we don’t need reminding about the horrific consequences of transmissable spongiform encephalopathies. Over one hundred and fifty britons have died of variant Creutzfeld-Jacob disease, and the images of cattle suffering the effects of BSE (and ministers feeding their daughters burgers) are still fresh in the mind. Part of the difficulty felt by scientists and government in handling the BSE crisis were due to these diseases being caused by a novel form of pathogenic entity, prions. Rather than encoding information facilitating their replication and transmission in a DNA or RNA genome like viruses and other pathogens, prions are proteins capable of self-replication. More specifically they are an aberrant conformation of a protein, capable of seeding the misfolding of the native form. In the case of the spongiform encephalopathies, the native ‘prion protein’ (a component of neuronal membranes, still of unknown function) is converted into a tangled form that is resistant to enzymatic degradation. This prion form is therefore capable of transmission through digestive systems that would normally degrade proteins. In the brain, the prions form toxic aggregations, causing neurodegeneration and death.

The idea that self-replicating proteins could act as elements of inheritance was revolutionary at the time, but prions are now being found to exist in many other contexts, and rather than acting as pathogens, their potential functions are yielding exciting insights into evolution and brain function.

In yeast, at least nine different proteins have been shown to form prions, and eighteen more contain prion-forming domains. These are often important proteins involved in the control of cellular regulation. The best characterised yeast prion, [ PSI+], is a form of a factor responsible for the termination of translation (the process of converting the sequence of messenger RNA transcripts into the amino acid sequence of protein), Sup35. [ PSI+] titrates normal Sup35 protein, lessening its level, and leading to an increase in translational read-through. This read-through effectively uncovers cryptic genetic variation. Genetic sequence that is not normally encoding protein sequence will be under less stringent evolutionary selection pressure than coding sequence. If this sequence is suddenly translated into protein in [ PSI+] cells it may, in a minority of cases, be beneficial for cell’s adaptation to their environment. Protein folding is mediated by ‘chaperone’ proteins, which are also closely involved in the response to environmental stresses. Hence, prion formation, a case of protein ‘mis-folding’, is more likely to occur during times of stress. Prions can therefore act as switches responsible for the sudden appearance of complex traits in response to environmental conditions. Although these possible ‘evolvability’ roles for prions in yeast are controversial, it appears that the prion-forming domains responsible for this capacity, have been conserved for long periods of evolutionary time, and do not generally have other major functions. Recently, [ PSI+] and another yeast prion have been shown to exist in wild yeast strains, strengthening the argument that they are not simply diseases or artifacts of laboratory culture.

Proteins that contain prion-forming domains are present in many branches of the tree of life. A particularly exciting example, found in the sea slug Aplysia, is an RNA-binding protein called CPEB. This protein is responsible for regulating the activation of the translation of mRNA transcripts in neuronal synapses in response to neurotransmitters, such as serotonin. The fact that it contains a prion-domain capable of propagating and stabilising a conformational change in the protein, and that this change equates to variant activities, has suggested an exciting answer to a hoary problem in neurobiology: the endurance of memories. Proteins and other cellular components are generally turned over in a matter of hours. How then can they be responsible for encoding memories that can last years? By CPEB undergoing a regulated prion-like polymerisation in response to synaptic transmission, a long-term memory of this stimulation can be stored. An equivalent CPEB in the fruit fly has recently been shown to be working in a similar way. It appears that this could be a more general mechanism for cellular memory storage in animal neurons.

A role for prions in memory is intriguing, as it hints at a reason why neurodegenerative diseases are so often associated with build ups of inactive mis-folded proteins. These ‘amyloid’ plaques are a feature of Alzheimer’s, Parkinson’s and Huntington’s diseases as well as the spongiform encephalopathies. Is this commonality a side effect of the brain normally permitting more regulated prion-like polymerisation events during memory formation?

The existence of self-replicating proteins, a new ‘epigenetic’ level of inheritance, has opened exciting new avenues of research. These new roles for prions in brain function and evolution could be just the tip of iceberg.

3 responses to “Prions, more than just brain rot.”

Great post, Habib!! I did look up Lindquist work, like you had suggested, but I was confused as to what exactly prions are… thank you! The more I learn about all these epigenetic mechanisms the more I’m awed at Mother Nature’s mysteries…